The secondary propargylated aminoindan rasagiline has been shown to be a selective inhibitor of MAO-B, and useful in treating Parkinson's disease and various other conditions. U.S. Pat. No. 5,532,415 discloses rasagiline (R(+)-N-propargyl-1-aminoindan (R(+)PAI)), its preparation, and various pharmaceutically acceptable salts thereof.
Another secondary propargylated aminoindan is R(+)-6-(N-methyl,N-ethyl-carbamoyloxy)-N′-propargyl-1-aminoindan, also known as (3R)-3-(prop-2-ynylamino)-2,3,-dihydro-1H-inden-5-yl ethylmethylcarbamate, which has been disclosed in PCT International Application Publication No. WO98/27055 (U.S. Pat. No. 6,303,650, issued Oct. 16, 2001 to Chorev). In addition, its preparation and its salts are disclosed, including the 1/2 L-tartrate salt. The 1/2 L-tartrate salt has been given the nonproprietary name ladostigil tartrate. Its CAS registry number is 209394-46-7. PCT International Application Publication No. WO98/27055 also discloses aminoindans having the formula:
wherein b is 1 or 2; m is 0-3; Y is O or S; X is halo; R1 is hydrogen or C1-4 alkyl; R2 is hydrogen, C1-4 alkyl, or optionally substituted propargyl; and R3 and R4 are each independently, C1-8 alkyl, C6-12 aryl, C6-12 aralkyl, each optionally halo substituted, or hydrogen. These compounds have been disclosed as being useful to treat depression, Attention Deficit Disorder (ADD), Attention Deficit and Hyperactivity Disorder (ADHD), Tourett's Syndrome, Alzheimer's Disease and other dementias.
These aminoindans have a chiral carbon to which the amino group is attached. Thus, in order to obtain enantiomerically pure compounds, when a racemic starting material is used enantiomeric resolution of these compounds is needed. This is normally the case when racemic 1-aminoindan is used as the starting material. U.S. Pat. No. 5,532,415 discloses that enantiomerically pure aminoindan derivatives may be obtained by optical resolution of racemic mixtures of R- and S-enantiomers of propargyl aminoindan derivatives. Such a resolution can be accomplished by any conventional resolution method well known to a person skilled in the art, such as those described in J. Jacques, A. Collet and S. Wilen, “Enantiomers, Racemates and Resolutions,” Wiley, N.Y. (1981). For example, the resolution may be carried out by preparative chromatography on a chiral column.
U.S. Pat. No. 5,532,415 describes how an enantiomerically pure propargyl aminoindan can also be prepared directly from the optically active R-enantiomer of 1-aminoindan by reaction with propargyl bromide or propargyl chloride or a propargyl sulfonate ester in the presence of an organic or inorganic base, and optionally in the presence of a suitable solvent. Suitable organic or inorganic bases for use in such reaction include, by way of example, triethylamine, pyridine, alkali metal carbonates, and bicarbonates. If the reaction is conducted in the presence of a solvent, the solvent may be chosen from, e.g., toluene, methylene chloride, and acetonitrile.
All of the aminoindan derivative separation methods mentioned in the prior art have their respective shortcomings, however. Chromatography is difficult to scale up because of the large quantities of solvents used, which are difficult to dispose of. Distillation is virtually impossible because of the high boiling points of the aminoindan derivatives. For example, even the primary aminoindan derivative 1-aminoindan boils at between 95° C. and 97° C. at 13 mbar, and at the same pressure the secondary and tertiary propargylated aminoindan derivatives will require higher temperature which is not industrially feasible. Selective extraction is also disadvantageous in that large amounts of solvent are required and large amounts of acidic solvents are produced which are difficult to dispose of. In addition, many steps are required for extraction, re-extraction and isolation of secondary propargyl aminoindan free base derivatives. An additional step of salt formation must be added after isolation of the secondary propargyl aminoindan free base derivatives in order to attain secondary propargyl aminoindan derivative salts.